1,5-substituted indol-2-yl amide derivatives

Abstract

The present invention relates to compounds of formula I wherein R 1 to R 4 and G are as defined in the description and claims and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

1. A compound of formula I, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of
 lower alkyl, lower alkenyl, lower alkynyl, 
 cycloalkyl, lower cycloalkylalkyl, 
 lower hydroxyalkyl, 
 lower alkoxyalkyl, 
 lower alkylsulfanylalkyl, 
 lower dialkylaminoalkyl, 
 lower dialkylcarbamoylalkyl, 
 phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy and lower hydroxyalkyl, 
 lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, 
 lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and 
 lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups; 
 
 R 2  is selected from the group consisting of hydrogen,
 lower alkyl, lower alkenyl, lower alkynyl, 
 cycloalkyl, lower cycloalkylalkyl, 
 lower hydroxyalkyl, lower alkoxyalkyl, 
 lower alkylsulfanylalkyl, 
 lower dialkylaminoalkyl, 
 lower dialkylcarbamoylalkyl, 
 phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy and lower hydroxyalkyl, 
 lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, 
 lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and 
 lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups; or 
 
 R 1  and R 2  together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur,
 said saturated or partly unsaturated heterocyclic ring 
 being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or 
 being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen; 
 
 R 3  is selected from the group consisting of lower hydroxyalkyl,
 lower cyanoalkyl, lower alkoxycarbonyl, 
 phenylsulfonyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; 
 phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; 
 lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; and 
 heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy, morpholino and cyano; 
 
 R 4  is hydrogen or halogen; 
 G is a group selected from 
 
       
         
           
           
               
               
           
         
       
       wherein
 m is 0, 1 or 2; 
 R 5  is selected from lower alkyl, lower halogenoalkyl, cycloalkyl, halogenocycloalkyl, lower cycloalkylalkyl and lower phenylalkyl; 
 n is 0, 1 or 2; 
 R 6  is lower alkyl; 
 p is 0, 1 or 2; 
 q is 0, 1 or 2; 
 A is selected from CR 12 R 12′ , O and S; 
 R 7 , R 7′ , R 8 , R 8′ , R 9 , R 9′ , R 12  and R 12′  independently from each other are selected from the group consisting of hydrogen, lower alkyl, hydoxy, halogen and dialkylamino, or 
 R 8  and R 12  together form a double bond; 
 R 10  is lower alkyl; 
 R 11  is C 3 -C 6 -alkyl; 
 
       and pharmaceutically acceptable salts thereof. 
     
     
       2. The compound according to  claim 1 , wherein R 1  and R 2  together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated or partly unsaturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. 
     
     
       3. The compound according to  claim 1 , wherein R 1  and R 2  together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenoalkyl, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen. 
     
     
       4. The compound according to  claim 1 , wherein R 1  and R 2  together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 4,4-difluoropiperidine and pyrrolidine. 
     
     
       5. The compound according to  claim 1 , wherein R 1  is selected from the group consisting of
 lower alkyl, lower alkenyl, lower alkynyl, 
 cycloalkyl, lower cycloalkylalkyl, 
 lower hydroxyalkyl, lower alkoxyalkyl, 
 lower alkylsulfanylalkyl, 
 lower dialkylaminoalkyl, lower dialkylcarbamoylalkyl, 
 phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenoalkoxy or lower hydroxyalkyl, 
 lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl, lower heteroarylalkyl wherein the heteroaryl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl and 
 lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two lower alkyl groups and 
 R 2  is hydrogen or lower alkyl. 
 
     
     
       6. The compound according to  claim 1 , wherein R 3  is selected from the group consisting of
 lower cyanoalkyl, lower alkoxycarbonyl, 
 phenylsulfonyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; 
 phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; 
 lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl; and 
 heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy, morpholino and cyano. 
 
     
     
       7. The compound according to  claim 1 , wherein R 3  is lower cyanoalkyl or lower alkoxycarbonyl. 
     
     
       8. The compound according to  claim 1 , wherein R 3  is phenylsulfonyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, cyano, lower halogenoalkyl, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. 
     
     
       9. The compound according to  claim 1 , wherein R 3  is lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. 
     
     
       10. The compound according to  claim 1 , wherein R 3  is phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower halogenoalkyl, cyano, lower alkoxy, lower halogenoalkoxy and lower hydroxyalkyl. 
     
     
       11. The compound according to  claim 1 , wherein R 3  is heteroaryl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower alkoxy, halogen, lower halogenoalkyl, lower halogenoalkoxy and cyano. 
     
     
       12. The compound according to  claim 11 , wherein R 3  is a heteroaryl group selected from pyridyl, pyrimidinyl, furanyl and thienyl. 
     
     
       13. The compound according to  claim 1 , wherein R 4  is hydrogen. 
     
     
       14. The compound according to  claim 1 , wherein G signifies 
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2 and R 5  is selected from lower alkyl, cycloalkyl, lower cycloalkylalkyl and lower phenylalkyl. 
     
     
       15. The compound according to  claim 1 , wherein R 5  is lower alkyl. 
     
     
       16. The compound according to  claim 1 , wherein G signifies 
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1 or 2, q is 0, 1 or 2, A is selected from CR 12 R 12′ , O and S and R 7 , R 7′ , R 8 , R 8′ , R 9 , R 9′ , R 12  and R 12′  independently from each other are selected from the group consisting of hydrogen, lower alkyl, hydoxy, halogen and dialkylamino, or R 8  and R 12  together form a double bond. 
     
     
       17. The compound according to  claim 16 , wherein A is CR 12 R 12′ , p is 0, q is 1 and R 7 , R 7′ , R 8 , R 8′ , R 9 , R 9′ , R 12  and R 12′  independently from each other are selected from hydrogen or lower alkyl. 
     
     
       18. The compound according to  claim 1 , selected from the group consisting of
 (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-benzenesulfonyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, 
 [1-benzyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-benzyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, 
 2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indole-1-carboxylic acid methyl ester, 
 [2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-acetonitrile, 
 [1-(3,5-difluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(3-trifluoromethoxy-phenyl)-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-trifluoromethoxy-phenyl)-1H-indol-2-yl]-methanone, 
 [1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 [1-(6-chloro-pyridin-3-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(2-methoxy-phenyl)-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[1-(4-fluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[1-(3-fluoro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, 
 [1-(3-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(3-methoxy-phenyl)-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-trifluoromethyl-phenyl)-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-phenyl-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-p-tolyl-1H-indol-2-yl]-methanone, 
 [1-(4-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone 
 [1-(3,4-dichloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 5-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-pyridine-2-carbonitrile, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-methanone, 
 3-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-benzonitrile, 
 4-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-benzonitrile, 
 [5-(1-isopropyl-piperidin-4-yloxy)-1-phenyl-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 [1-(4-chloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 [1-(3,4-dichloro-phenyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 [5-(1-isopropyl-piperidin-4-yloxy)-1-p-tolyl-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 [5-(1-isopropyl-piperidin-4-yloxy)-1-(4-methoxy-phenyl)-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 4-[5-(1-isopropyl-piperidin-4-yloxy)-2-(morpholine-4-carbonyl)-indol-1-yl]-benzonitrile, 
 5-[2-(4,4-difluoro-piperidine-1-carbonyl)-5-(1-isopropyl-piperidin-4-yloxy)-indol-1-yl]-2-fluoro-benzonitrile, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(2-methoxy-pyrimidin-5-yl)-1H-indol-2-yl]-methanone, 
 4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-thiophen-3-yl-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyridin-2-yl-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-thiophen-2-yl-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-(6-morpholin-4-yl-pyridin-3-yl)-1H-indol-2-yl]-methanone, 
 (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyridin-3-yl-1H-indol-2-yl]-methanone, 
 [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone, 
 [6-bromo-1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone, 
 [6-bromo-1-(2-chloro-pyridin-4-yl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 [5-(1-cyclobutyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone, 
 (4-hydroxy-4-methyl-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-methanone, and 
 [5-(1-cyclobutyl-piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indol-2-yl]-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone, 
 
       and pharmaceutically acceptable salts thereof. 
     
     
       19. A process for the manufacture of compounds according to formula Ia or formula Ib, comprising the steps of:
 a) treating a compound of the formula II 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 4  are as defined in  claim 1 , with a suitable base in a suitable solvent under anhydrous conditions and reacting the intermediate anion with an alkylating or acylating agent of the formula III
   R 3 —X   III, 
 
       wherein X signifies a leaving group and R 3  is selected from the group consisting of lower hydroxyalkyl, lower cyanoalkyl, optionally substituted lower phenylalkyl, lower alkoxycarbonyl and optionally substituted phenylsulfonyl, 
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from the group consisting of lower hydroxyalkyl, lower cyanoalkyl, optionally substituted lower phenylalkyl, lower alkoxycarbonyl and optionally substituted phenylsulfonyl,
 and if desired, 
 converting the compound obtained into a pharmaceutically acceptable acid addition salt, or alternatively, 
 b) reacting a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 4  are as defined in  claim 1 , with an optionally substituted phenyl- or heteroaryl boronic acid of the formula IV 
       
         
           
           
               
               
           
         
       
       wherein R 3  signifies optionally substituted aryl or heteroaryl, in the presence of a catalyst and basic conditions to obtain a compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 3  signifies optionally substituted aryl or optionally substituted heteroaryl, and if desired,
 converting the compound obtained into a pharmaceutically acceptable acid addition salt. 
 
     
     
       20. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or adjuvant. 
     
     
       21. A method for the treatment of obesity in a human being or animal, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  in combination or association with a therapeutically effective amount of a compound selected from the group consisting of a lipase inhibitor, an anorectic agent, a selective serotonin reuptake inhibitor and an agent that stimulates metabolism of body fat, to said human being or animal in need thereof. 
     
     
       22. A method of treatment of type II diabetes in a human being or animal, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  in combination or association with a therapeutically effective amount of an anti-diabetic agent to said human being or animal in need thereof.